tbuckley/cabot-search huggingface dataset:
Abstract 2422: Migration of V600E-expressing cells is suppressed by ERK-dependent feedback inhibition of RAC1 and rescued in melanoma by secondary mutations
Authors: Sunyana Gadal, Jacob A. Boyer, Hongyan Li, Ning Fan, Eric Chan, Yevgeniy Romin, Elisa De Stanchina, Rona Yeager, Marcus Bosenberg, Katia M. Todorova, Neal Rosen
Journal: Cancer Research (2022)

Abstract Oncogenic activation of ERK occurs in as many as 50% of human tumors and in the majority of melanomas. Activated BRAF V600E hyperactivates ERK signaling and causes ERK dependent dysregulation of proliferation. However, BRAF V600E alone is insufficient to drive melanoma formation in genetically engineered mice models. Moreover, 82% of benign nevi harbor BRAF V600E mutations. In contrast, in BRAF V600E/PTEN-/- GEMM models, rapid onset of aggressive and disseminated melanomas occurs. We show here that cell migration and invasion of melanocytes expressing BRAFV600E is depressed in vitro and in vivo and significantly accelerated by pharmacologic inhibition of ERK signaling or by deletion of PTEN. Upon ERK inhibition, cells lose their cell-cell junctions and become single cells with actin rich protrusions and a mesenchymal morphology. ERK pathway activation affects each step of the migration cycle, impeding cell spreading, assembly of stress fibers, and focal contact formation, all of which are associated with decreased mobility and invasion. Hyperactivation of ERK signaling by BRAF V600E has been shown to cause potent feedback inhibition of RTK signaling and wild type RAS. We now show that this is associated with feedback inhibition of RAC1, a RAS-like small GTPase required for cell migration. Moreover, ERK pathway inhibition reactivates RAC in an RTK-dependent manner. Consistent with these findings, expression of RAC1 P29S, an activating mutant, and overexpression of PREX2, an activator of RAC1, both rescue migration in BRAF V600E cells, as does loss of PTEN expression, which converges with RAC1 activation downstream. Taken together, these data suggest that whereas hyperactivation of ERK signaling by BRAFV600E dysregulates proliferation, ERK dependent feedback inhibition of RAC1 inhibits cell mobility and invasiveness and prevents full transformation. Selection of secondary genetic events that overcome or bypass RAC1 feedback is thus required for full transformation. In support of this view, RAC1 mutation, PTEN loss, or PREX2 amplification occurs in 38% of human melanomas. Thus, oncogene induced feedback may be deleterious and directs tumor evolution by causing selection of mutations that restore functions necessary for transformation Citation Format: Sunyana Gadal, Jacob A. Boyer, Hongyan Li, Ning Fan, Eric Chan, Yevgeniy Romin, Elisa De Stanchina, Rona Yeager, Marcus Bosenberg, Katia M. Todorova, Neal Rosen. Migration of V600E-expressing cells is suppressed by ERK-dependent feedback inhibition of RAC1 and rescued in melanoma by secondary mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2422.
Efficacy and Safety of Ripretinib in Chinese Patients with Advanced Gastrointestinal Stromal Tumors as a Fourth- or Later-Line Therapy: A Multicenter, Single-Arm, Open-Label Phase II Study
Authors: Jian Li, Shirong Cai, Yongjian Zhou, Jun Zhang, Ye Zhou, Hui Cao, Xin Wu, Yanhong Deng, Zhao Huang, Juan Dong, Lin Shen
Journal: Clinical Cancer Research (2022)

Abstract Purpose: This is a phase II multicenter, single-arm, open-label study assessing the efficacy, safety, and pharmacokinetics (PK) of ripretinib in Chinese patients with advanced gastrointestinal stromal tumor (GIST) as a fourth- or later-line therapy. It was designed to show consistency with the phase III INVICTUS study. Patients and Methods: Patients with disease progression on (or intolerance to) prior imatinib, sunitinib, and at least one other drug were recruited to receive ripretinib 150 mg once daily continuously in 28-day cycles. The primary endpoint was progression-free survival (PFS) based on independent radiologic review (IRR). Secondary efficacy endpoints included objective response rate (ORR) based on IRR and overall survival. Safety endpoints included the incidence and severity of adverse events (AE). Results: Between April 2020 and August 2020, 39 patients were enrolled. All were included in the safety analysis while 38 were included in the efficacy analysis. By primary data cut-off (February 26, 2021), the median PFS [90% confidence interval (CI)] was 7.2 (2.9–7.3) months; the lower bound of the 90% CI exceeded 1 month, fulfilling the standard of bridging success. The ORR (95% CI) based on IRR was 18.4% (7.7%–34.3%). Treatment-related treatment-emergent AEs (TRAE) were reported in 37 (94.9%) patients. The majority of TRAEs were of grade 1/2. A total of 6 patients (15.4%) experienced grade 3/4 TRAEs. Conclusions: The results demonstrated that ripretinib can clinically improve the outcomes of Chinese patients with advanced GIST as a fourth- or later-line therapy. The efficacy, safety, and PK profiles of ripretinib are consistent with those in the global patient population.
Olutasidenib (FT-2102) in patients with relapsed or refractory <i>IDH1</i>-mutant glioma: A multicenter, open-label, phase Ib/II trial
Authors: Macarena I de la Fuente, Howard Colman, Mark Rosenthal, Brian A Van Tine, Danijela Levacic, Tobias Walbert, Hui K Gan, Maria Vieito, Mohammed M Milhem, Kathryn Lipford, Sanjeev Forsyth, Sylvie M Guichard, Yelena Mikhailov, Alexander Sedkov, Julie Brevard, Patrick F Kelly, Hesham Mohamed, Varun Monga
Journal: Neuro-Oncology (2022)

Olutasidenib (FT-2102) is a highly potent, orally bioavailable, brain-penetrant and selective inhibitor of mutant isocitrate dehydrogenase 1 (IDH1). The aim of the study was to determine the safety and clinical activity of olutasidenib in patients with relapsed/refractory gliomas harboring an IDH1R132X mutation.This was an open-label, multicenter, nonrandomized, phase Ib/II clinical trial. Eligible patients (≥18 years) had histologically confirmed IDH1R132X-mutated glioma that relapsed or progressed on or following standard therapy and had measurable disease. Patients received olutasidenib, 150 mg orally twice daily (BID) in continuous 28-day cycles. The primary endpoints were dose-limiting toxicities (DLTs) (cycle 1) and safety in phase I and objective response rate using the Modified Response Assessment in Neuro-Oncology criteria in phase II.Twenty-six patients were enrolled and followed for a median 15.1 months (7.3‒19.4). No DLTs were observed in the single-agent glioma cohort and the pharmacokinetic relationship supported olutasidenib 150 mg BID as the recommended phase II dose. In the response-evaluable population, disease control rate (objective response plus stable disease) was 48%. Two (8%) patients demonstrated a best response of partial response and eight (32%) had stable disease for at least 4 months. Grade 3‒4 adverse events (≥10%) included alanine aminotransferase increased and aspartate aminotransferase increased (three [12%], each).Olutasidenib 150 mg BID was well tolerated in patients with relapsed/refractory gliomas harboring an IDH1R132X mutation and demonstrated preliminary evidence of clinical activity in this heavily pretreated population.
Abstract 3687: Implementing geospatial technology to understand the prostate cancer health burdens and socioeconomic status in Alabama
Authors: Ram Alagan, Seela Aladuwaka, Rajesh Singh, Upender Manne, Manoj K. Mishra
Journal: Cancer Research (2022)

Abstract Socioeconomic status and health disparities are a significant liability for the prevalence of many diseases, including cancer. Among many contributing factors, lack of socioeconomic advancement and inequality in resource distribution is closely associated with prostate cancer occurrence. The State of Alabama has one of the highest rates of prostate cancer in the nation and the third cancer epidemic at the state level. Due to widespread disparities in infrastructure development, political willpower, equal healthcare, and education opportunity, Alabama's Black Belt region has been further divided by socioeconomic statuses among the majority (Whites) and minority (African American) populations. The purpose of this research is to recognize Alabama's health burdens and socioeconomic status using geo-spatial technology (GIS) to examine prostate cancer health disparity. GIS has become a valuable decision-making tool in understanding the public health care sectors, including prostate cancer prevalence. GIS supports assembling spatial and non-spatial data, displays the spatial distribution of health disparities, and underlines further interconnectivity of policy-related questions. This research incorporates county-level prostate cancer data using GIS and outlining the correlation between prostate cancer prevalence and socioeconomic factors to understand Alabama's cancer health disparity and equity. A combination of socioeconomic factors and state and federal-level cancer epidemic data sources underline Alabama's black belt region (predominantly African American) prostate cancer prevalence is higher than the non-black belt. The GIS analysis demonstrated that effective cancer prevention programs are needed to eliminate health disparities and enhance health equity among underserved populations of Alabama. Citation Format: Ram Alagan, Seela Aladuwaka, Rajesh Singh, Upender Manne, Manoj K. Mishra. Implementing geospatial technology to understand the prostate cancer health burdens and socioeconomic status in Alabama [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3687.
Abstract 3146: EGFL6 induces immunosuppressive functions of tumor-associated myeloid cells and mediates resistance to anti-PDL1 therapy
Authors: Sarah Sinno, Shoumei Bai, Claudia Coronnello, Anda Vlad, Ronald J. Buckanovich, Sandra Cascio
Journal: Cancer Research (2022)

Abstract Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) are critical negative regulators of immunity in cancer. Understanding factors which regulate these cells could result in the identification of new approaches to enhance anti-tumor immunotherapy. One such factor is Epidermal growth factor-like 6 (EGFL6). EGFL6 is a secreted factor known to promote cancer stem like cell migration and regulate cancer cell differentiation. Similarly, EGFL6 promotes endothelial cell migration and proliferation. Indicating a potential role for EGFL6 as a myeloid cell regulatory factor, we found that mice which overexpress Egfl6 have an increased numbers of granulocytes and monocytes in both the bone marrow and spleen. In vitro and ex-vivo analysis indicated that EGFL6, via binding with beta integrins and activation of Syk/ERK signaling, (i) acts as a chemotactic factor for human myeloid cells migration and (ii) promotes their differentiation toward a suppressive state. Suggesting an important role in promoting an immunosuppressive tumor microenvironment (TME), using two syngeneic mouse models of ovarian cancer, we found that expression of Egfl6 in tumor cells resulted in increased accumulation of intra-tumoral MDSCs and TAMs and fewer cytotoxic CD8+ T cells. This was associated with increased tumor growth and shortened animal survival. Gene expression profiling and flow cytometry analysis of tumor infiltrating myeloid cells indicated that Egfl6 induced the expression of immunosuppressive factors, including CXCL2, IL-10 and PD-L1. Consistent with Egfl6 driving an immune suppressive TME, EGFL6 expression in an otherwise immune ‘hot’/anti-PD-L1 responsive tumor model completely inhibited response to anti-PD-L-1 therapy. We are currently evaluating the impact of Egfl6 neutralizing antibody on the efficacy of ICI therapy and anti-tumor immunity. Combined our data show that EGFL6 acts as a chemotactic factor to both recruit myeloid cells to the ovarian TME and subsequently promotes their differentiation to an immunosuppressive phenotype. This suggests EGFL6 is a potential novel therapeutic target to ovarian tumor mediated immunosuppression and enhance response to immune therapy in ovarian cancer patients. Citation Format: Sarah Sinno, Shoumei Bai, Claudia Coronnello, Anda Vlad, Ronald J. Buckanovich, Sandra Cascio. EGFL6 induces immunosuppressive functions of tumor-associated myeloid cells and mediates resistance to anti-PDL1 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3146.
Abstract 2953: Subtype-specific and structure variation induced 3D genome alteration in acute myeloid leukemia
Authors: Jie Xu, Fan Song, Baozhen Zhang, Huijue Lyu, Mikoto Kobayashi, Ziyu Zhao, Ye Hou, Xiaotao Wang, Yu Luan, Bei Jia, Lena Stasiak, Qixuan Wang, Qi Jin, Qiushi Jin, Yihao Fu, Ross C. Hardison, Sinisa Dovat, Leonidas C. Platanias, Yue Yang, Tomoko Yamada, Aaron D. Viny, Ross L. Levine, David F. Claxton, James R. Broach, Hong Zheng, Feng Yue
Journal: Cancer Research (2022)

Abstract Acute myeloid leukemia (AML) represents a set of heterogeneous myeloid malignancies hallmarked by mutations in epigenetic modifiers, transcription factors, and kinases that can cause epigenetic reshaping. It is unclear to what extent AML mutations drive chromatin 3D structure alteration and contribute to myeloid transformation. We first performed Hi-C and whole-genome sequencing in 25 AML patient samples and seven healthy donor samples, and identified recurrent alterations of A/B compartments, TADs, and chromatin loops that are unique to different subtypes. To investigate how altered chromatin organization contributes to transcriptional misregulation, we performed RNA-Seq, ATAC-Seq and CUT&amp;ag for CTCF, H3K27ac, and H3K27me3 in the same AML samples. We identified extensive and recurrent AML-specific promoter-enhancer and promoter-repressor loops. We performed both CRISPR deletion and interference experiments and validated two repressor loops that downregulated cancer related genes IKZF2 and RTTN. Furthermore, by using our recently developed algorithm, we identified structural variation-induced enhancer-hijacking and repressor-hijacking events in AML samples. We further demonstrated the role of hijacked enhancers in AML cell growth by CRISPR screening, and the role of hijacked repressors by CRISPR de-repression. We performed whole-genome bisulfite sequencing in 20 AML and normal samples, and showed the delicate relationship between DNA methylation, CTCF binding and 3D genome structure. Finally, by treating the AML cells with the DNA hypomethylating agent and performing triple knockdown of DNMT1/3A/3B, we demonstrated the impact of altered DNA methylation on gene expression and 3D genome organization. Overall this study provides an invaluable resource for leukemia studies and also highlighted the role of repressor-loops and hijacked cis-elements in gene regulation and human diseases. Citation Format: Jie Xu, Fan Song, Baozhen Zhang, Huijue Lyu, Mikoto Kobayashi, Ziyu Zhao, Ye Hou, Xiaotao Wang, Yu Luan, Bei Jia, Lena Stasiak, Qixuan Wang, Qi Jin, Qiushi Jin, Yihao Fu, Ross C. Hardison, Sinisa Dovat, Leonidas C. Platanias, Yue Yang, Tomoko Yamada, Aaron D. Viny, Ross L. Levine, David F. Claxton, James R. Broach, Hong Zheng, Feng Yue. Subtype-specific and structure variation induced 3D genome alteration in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2953.
Abstract 252: STAT3 signaling in the tumor microenvironment promotes primary gastric cancer growth and metastasis formation
Authors: Moritz Eissmann, Anne Huber, Amr Allam, Christine Dijkstra, Matthias Ernst
Journal: Cancer Research (2022)

Abstract Tumor cell intrinsic activation of Signal Transducer and Activator of Transcription 3 (STAT3) signaling has been shown to promote stemness, tumorigenesis and cancer therapy resistance. Therefore, Stat3 inhibitors are being developed and tested pre-clinically and in clinical trials for multiple solid cancers. Importantly, STAT3 signaling also occurs in the non-tumor cells within the tumor microenvironment (TME). The effect of Stat3 signaling within the TME on primary gastric cancers (GC), metastasis formation and therapy responses is unknown. Here, we describe a novel genetically defined, tumor organoid-driven, transplantable, orthotopic gastric cancer model that represents gastric carcinomas with associated metastasis formation in immune competent recipient mice. Utilizing our murine GC organoid model in subcutaneous allograft experiments, we showed that established GC tumors respond to pharmacological Stat3 inhibition. This anti-tumor effect is primarily driven by inhibition of the Stat3 signaling in the TME as tumor growth was increased in Stat3 high TME recipients, while tumor growth was inhibited in Stat3-signaling reduced Stat3+/- mice. Furthermore, Crisp-Cas9 -mediated Stat3 knockout in the GC organoids did not alter their in vitro growth potential. Stat3KO GC allograft tumor growth was not changed compared to Stat3WT GC tumors grown in wildtype host mice. Collectively, this suggests that inhibition of Stat3 signaling within the TME but not the tumor cell intrinsic Stat3 reduction confer anti-tumor responses. Through gastric serosa transplantation of the murine GC organoids into Stat3-elevated gp130FF mutant mice, we confirmed that high Stat3 signaling within the TME promotes distal metastasis formation to the liver. Taken together, we show that Stat3 signaling represents a therapy target, that predominantly acts through the TME. Better understanding of the signaling within the TME in primary and metastatic GC lesions will allow identification of novel tumor cell and TME-centric therapy targets. Combination of therapies targeting tumor cell intrinsic vulnerabilities with novel pro-tumorigenic TME -targeting agents could help to improve responses against primary and metastatic disease and therefore improve outcome for the worst prognosis patients. Citation Format: Moritz Eissmann, Anne Huber, Amr Allam, Christine Dijkstra, Matthias Ernst. STAT3 signaling in the tumor microenvironment promotes primary gastric cancer growth and metastasis formation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 252.
Phase II Study of TQB2450, a Novel PD-L1 Antibody, in Combination with Anlotinib in Patients with Locally Advanced or Metastatic Soft Tissue Sarcoma
Authors: Jiayong Liu, Tian Gao, Zhichao Tan, Shu Li, Jie Xu, Chujie Bai, Ruifeng Xue, Lu Xie, Lu Zhang, Zhengfu Fan, Wei Guo
Journal: Clinical Cancer Research (2022)

Abstract Purpose: To explore the efficacy and safety of TQB2450 combined with anlotinib in patients with locally advanced or metastatic soft-tissue sarcoma (LA/M STS). Patients and Methods: This was a single arm phase II study (TQB2450-Ib-02 study) performed at two hospitals in China to assess the potency of TQB2450 combined with anlotinib in patients with LA/M STS. Patients were previously unresponsive to at least one chemotherapy regimen. Anlotinib (12 mg every day) was administered orally from day 1 to day 14 every 3 weeks. TQB2450 was administered by intravenous infusion at 1,200 mg on day 1 every 3 weeks. The primary endpoint was the objective response rate (ORR). The secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety. Results: Between January 2019 and June 2020, 30 patients were enrolled. The ORR was 36.67% and the DCR was 76.67%. The median PFS was 7.85 months [95% confidence interval (CI), 2.89–23.06] and the median OS was not reached [95% CI, 10.58–not estimable (NE)]. Among the patients with alveolar soft part sarcoma (ASPS; 12/30, 40%), the ORR was 75% and the median PFS was 23.06 months (95% CI, 8.97–NE). The most common treatment related adverse events were hypothyroidism (76.67%), hypertriglyceridemia (63.33%), hypercholesterolemia (60.00%), and elevated blood lactate dehydrogenase (53.33%). Conclusions: The study showed the promising activity in patients with ASPS, also indicating the trend of treatment efficacy in other sarcomas. The toxicity was tolerable. More studies with larger sample size and controlled arm were warranted.
Abstract 3623: Targetable cofactor landscape of transcription factors in human cancers
Authors: Venu Thatikonda, Jesse Lipp, Andreas Schlattl, Daniel Gerlach, Alexandra Popa
Journal: Cancer Research (2022)

Abstract Transcription factors (TF) are proteins that bind to DNA to regulate target gene expression and play a crucial role in maintaining tumor initiating and maintenance programs. However, except for a small fraction, it is difficult to directly target TF proteins due to lack of defined pockets and inherent protein-DNA, protein-protein interactions. In many cases, TF activity is tuned via cofactors, which e.g. dimerize to bind DNA (MYC/MAX) or maintain active TF protein turnover (HIF1A/EGLN1, MYC/HDAC2). Identifying such targetable cofactors of TFs will open new opportunities to target oncogenic TFs in cancers. Genome-scale CRISPR knock-out screens have been proven to be a valuable resource for identifying targets and biomarkers in cancers. In this work, we developed a framework called CONTEXT (COfactor depeNdencies in high Transcription factor EXpression phenoType) utilizing functional genomic screens and matched TF expression data. In CONTEXT, we aim to identify cofactor dependencies associated with TF activities using 859 cell lines spanning 28 cancer types. We further utilized patient cancer gene expression data from the TCGA project, to prioritize clinically relevant TF-cofactor associations. In total, we identified 1,003 TF-cofactor associations which involve 196 and 503 unique TFs and cofactors, respectively. Our approach reliably identified previously known TF-cofactor associations e.g. HIF1A/EGLN1, HIF1A/VHL, TEAD1/JUN but also previously unknown associations such as TEAD1/RAC1 or TEAD1/PTK2. Our analysis and validations provide a framework for the identification of potential cofactors of TFs which are crucial for the development and progression of cancer. We anticipate the cofactor dependencies from this resource to guide early stage drug development and inform on potential combination therapies in resistant phenotypes. Citation Format: Venu Thatikonda, Jesse Lipp, Andreas Schlattl, Daniel Gerlach, Alexandra Popa. Targetable cofactor landscape of transcription factors in human cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3623.